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  • The second member of transient receptor potential-melastatin channel family protects hearts from ischemia-reperfusion injury.

The second member of transient receptor potential-melastatin channel family protects hearts from ischemia-reperfusion injury.

American journal of physiology. Heart and circulatory physiology (2013-02-05)
Barbara A Miller, JuFang Wang, Iwona Hirschler-Laszkiewicz, Erhe Gao, Jianliang Song, Xue-Qian Zhang, Walter J Koch, Muniswamy Madesh, Karthik Mallilankaraman, Tongda Gu, Shu-jen Chen, Kerry Keefer, Kathleen Conrad, Arthur M Feldman, Joseph Y Cheung
ABSTRACT

The second member of the transient receptor potential-melastatin channel family (TRPM2) is expressed in the heart and vasculature. TRPM2 channels were expressed in the sarcolemma and transverse tubules of adult left ventricular (LV) myocytes. Cardiac TRPM2 channels were functional since activation with H2O2 resulted in Ca(2+) influx that was dependent on extracellular Ca(2+), was significantly higher in wild-type (WT) myocytes compared with TRPM2 knockout (KO) myocytes, and inhibited by clotrimazole in WT myocytes. At rest, there were no differences in LV mass, heart rate, fractional shortening, and +dP/dt between WT and KO hearts. At 2-3 days after ischemia-reperfusion (I/R), despite similar areas at risk and infarct sizes, KO hearts had lower fractional shortening and +dP/dt compared with WT hearts. Compared with WT I/R myocytes, expression of the Na(+)/Ca(2+) exchanger (NCX1) and NCX1 current were increased, expression of the α1-subunit of Na(+)-K(+)-ATPase and Na(+) pump current were decreased, and action potential duration was prolonged in KO I/R myocytes. Post-I/R, intracellular Ca(2+) concentration transients and contraction amplitudes were equally depressed in WT and KO myocytes. After 2 h of hypoxia followed by 30 min of reoxygenation, levels of ROS were significantly higher in KO compared with WT LV myocytes. Compared with WT I/R hearts, oxygen radical scavenging enzymes (SODs) and their upstream regulators (forkhead box transcription factors and hypoxia-inducible factor) were lower, whereas NADPH oxidase was higher, in KO I/R hearts. We conclude that TRPM2 channels protected hearts from I/R injury by decreasing generation and enhancing scavenging of ROS, thereby reducing I/R-induced oxidative stress.

MATERIALS
Product Number
Brand
Product Description

Supelco
Clotrimazole, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Clotrimazole
Clotrimazole for peak identification, European Pharmacopoeia (EP) Reference Standard
Clotrimazole, European Pharmacopoeia (EP) Reference Standard